In 2015 in the United States 5.3 million people were estimated to suffer from Alzheimer?s disease, which is also the 6th leading cause of death and lacks treatments to prevent or alter its progression. Recent advances in understanding of the underlying molecular mechanisms of the disease reinforce the role of soluble amyloid- beta (A?) oligomers as primary neurotoxins responsible for the acute cognitive deficits and progressive neurodegeneration of Alzheimer?s disease. However, current A? immunotherapies in clinical development primarily target A? monomers or fibrillic A? species; none have selectivity for soluble A? oligomers. Although solanezumab and aducanumab have shown some evidence of therapeutic benefit in prodromal and/or mild Alzheimer?s disease patients, therapeutic benefit remains to be confirmed, and on the whole results for A? immunotherapies in clinical testing have been disappointing, and indicate they target the wrong A? species. Moreover, all A? immunotherapies in an IgG1 framework that bind fibrillic A? have displayed ARIA-E adverse effects in clinical trials. We propose an A? immunotherapy targeting soluble A? oligomers that would be expected to display superior efficacy and better safety than A? immunotherapies currently in development. ACU193 is a proprietary, affinity matured, humanized, IgG2 monoclonal antibody that has high selectivity for soluble A? oligomers versus monomeric and fibrillic A?, and shows potent in vitro and in vivo efficacy. ACU193 has demonstrated in vivo biochemical and behavioral efficacy in Alzheimer?s disease mouse models, crosses the blood-brain barrier, and forms complexes with soluble A? oligomers in the brain. ACU193 has excellent pharmacokinetics, biodistribution and brain penetration properties in four animal species. Exploratory toxicity studies in rhesus monkeys and in vitro protein binding studies reveal an excellent safety profile for ACU193. A high producing, stable cell line is suitable for production of ACU193. ACU193 is a highly promising IND-track A? immunotherapy that is expected to provide acute cognitive benefits, slow disease progression, and be safe and well tolerated in Alzheimer?s disease patients. The aims of this application are to complete pre-clinical chemistry, manufacturing and control studies, toxicology and pharmacokinetic studies, submit an IND dossier to the FDA, and then conduct first in human clinical safety trials for ACU193. Human trials of ACU193 will represent the first test of the hypothesis that soluble A? oligomers are the primary molecular cause of Alzheimer?s disease, the results of which may dramatically expand understanding of the pathophysiology of Alzheimer?s disease. The proposed clinical testing of ACU193 consists of Phase 1a/1b and /2a studies of the safety, tolerability, pharmacokinetics, pharmacodynamics and cognitive effects of ACU193 in patients with prodromal or mild Alzheimer disease.